Treatment of hypothyroidism with levothyroxine.
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Humans↗
Biomedical subjects
A G Smals
Publications and source records attributed to A G Smals.
Hypotensive effects of ovine and human corticotrophin-releasing factors in man.
The haemodynamic effects of i.v. bolus injections of 100 and 200 micrograms ovine CRF and human CRF in man have been compared. Neither ovine CRF 100 micrograms nor human CRF 100 micrograms caused a significant change in blood pressure, although the pulse rate was increased in all the subjects tested. The mean maximum increase in pulse rate after human CRF was almost twice that after ovine CRF (21 vs 12 beats X min-1; p less than 0.05). After 200 micrograms ovine CRF in all subjects the diastolic blood pressure declined gradually from 77 mm Hg to a nadir of 67 mm Hg at 22 min (p less than 0.002). After 200 micrograms human CRF diastolic blood pressure fell from 78 mm Hg to a nadir of 61 mm Hg at 6 min (p less than 0.002); the fall after human CRF was significantly greater than after ovine CRF (p less than 0.05). After 200 micrograms ovine CRF there was a slight increase in pulse rate lasting for 6 min, and after 200 micrograms human CRF there was a marked (reflex) tachycardia for 30 min. Only after the highest dose of human CRF did a slight increase in systolic blood pressure occur. The haemodynamic effects of both doses of human CRF were accompanied by significant increases in plasma noradrenaline concentrations, which were significantly greater after the higher dose.
Adolescent↗
Enhancement of the ACTH response to human CRH by pretreatment with the antiglucocorticoid RU-486.
The response of ACTH to an i.v. bolus injection of 100 micrograms human CRH at 09.00 h was investigated in five healthy men with and without pretreatment with the antiglucocorticoid RU-486 100 mg given orally 7 h before the injection of CRH. In all five subjects the plasma cortisol level immediately before CRH administration at 09.00 h was significantly higher after pretreatment with the antiglucocorticoid (17.1 vs 11.1 micrograms/100 ml). Despite this higher baseline cortisol level, in all subjects the maximal CRH-induced ACTH increase was more pronounced after RU-486 loading (delta max ACTH 39 vs 26 pg/ml). This observation proves that in man physiological concentrations of cortisol determine the response of the pituitary to CRH. Furthermore, the findings suggest reduced circulating glucocorticoid activity after administration of 100 mg RU-486, not completely compensated by an increase in plasma cortisol.
Adrenocorticotropic Hormone↗
Progesterone receptor activity and relapse-free survival in patients with primary breast cancer: the role of adjuvant chemotherapy.
The prognostic significance of progesterone receptor activity (PgR) with regard to the estimated relapse-free survival (RFS) was studied in 350 one-center patients with primary breast cancer. All receptor assays were performed in one laboratory; PgR levels greater than 10 fmol/mg protein were considered positive. Univariate as well as multivariate statistical analyses were used to examine the prognostic significance of several variables. Eighty-nine of the 350 patients received adjuvant CMF chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil). The median observation period was 69 months (range 12-125 months). In the group of 261 patients who did not receive adjuvant CMF, the PgR-status lacked prognostic significance; only the lymph node status significantly affected the RFS (p less than 0.00001). In contrast, in the CMF-treated group of patients, the PgR-status was the most powerful predictor of recurrence (p less than 0.001). Premenopausal CMF-treated patients with PgR+ tumors had a significantly longer RFS than those with PgR- tumors (p less than 0.02). The present data urge the need for a reappraisal of the prognostic significance of PgR and of the mechanism of action of adjuvant chemotherapy in primary breast cancer.
Analysis of Variance↗
Coexistence of hypothalamic and pituitary failure after successful pituitary surgery in Cushing's disease?
The type of secondary adrenal failure, which occurs after successful pituitary surgery in Cushing's disease was studied using CRH administration. Eight patients with Cushing's disease were studied in the immediate postoperative period (9-18 days) of successful pituitary surgery. The results in these patients were compared with those in 13 healthy subjects, 7 patients with secondary adrenal failure of the pituitary type and 9 patients with secondary adrenal failure of the hypothalamic type. In all postoperative patients with Cushing's disease, except one, clear ACTH and cortisol responses occurred after CRH, demonstrating hypothalamic adrenal failure in these patients. This demonstration of hypothalamic adrenal failure after neurosurgery strongly argues against a pivotal role for endogenous CRH in the pathogenesis of Cushing's disease in these patients. The mean ACTH response to CRH in the postoperative patients with Cushing's disease was significantly lower than that in patients with adrenal failure of the hypothalamic type. This suggests the presence of pituitary failure in the postadenomectomy patients. In conclusion, this study provides arguments that the secondary adrenal failure after adenomectomy in Cushing's disease is caused by both hypothalamic and pituitary failure.
Adrenal Insufficiency↗
Reciprocal inhibition of the long-acting luteinizing hormone releasing hormone agonist Buserelin and human chorionic gonadotropin in stimulating Leydig cell steroidogenesis.
The interference between human chorionic gonadotropin (hCG, Pregnyl, Organon 1500 IU i.m.) and the long acting LHRH agonist Buserelin (500 micrograms s.c.) in stimulating Leydig cell steroidogenesis was studied in 6 eugonadal men. Simultaneous administration of a single injection of the agonist (LHRH alpha) and hCG blunted the plasma testosterone response observed 24 h after LHRH alpha alone, enhanced the secretion of oestradiol without affecting 17-hydroxy-progesterone and aggravated the late steroidogenic block at the 17,20-lyase locus. As compared to hCG alone, combined LHRH alpha and hCG administration also decreased the maximum and 48 h testosterone increments and the testosterone production reflected by the area under the curve, enhanced the production of oestradiol and again aggravated the 17,20-lyase lesion. The data show that the long acting agonist LHRH alpha and hCG reciprocally inhibit their stimulatory effect on Leydig cell testosterone secretion probably by a suppressive effect of oestrogens on the conversion of C21- to C19-steroids. The mechanism underlying this reciprocal inhibition remains to be elucidated.
17-alpha-Hydroxyprogesterone↗
Progesterone receptor activity and the response to the first endocrine therapy in advanced breast cancer.
The predictive value of the progesterone receptor activity (PgR) was studied in a group of 84 patients with estradiol receptor (ER) positive advanced breast cancer who received their first endocrine treatment (tamoxifen or ovariectomy), with special emphasis on the timing of the receptor analysis. All patients were treated at 1 center and receptor analyses performed in 1 laboratory. In the group of 27 patients with PgR analysis performed immediately prior to the start of treatment, 14 out of 18 PgR+ve and only 2 out of 9 PgR-ve patients responded (P less than 0.02). In contrast, when PgR was analysed greater than 6 months prior to the start of treatment, the response rates for PgR+ve and PgR-ve patients did not differ significantly: 55% vs. 33% respectively. With regard to quantitative rather than qualitative PgR data, PgR levels exceeding 100 fmol/mg protein irrespective of ER levels, are an excellent indicator of hormonal responsiveness with a response rate of more than 80%, even if PgR analyses are performed long before the start of treatment.
Breast Neoplasms↗
The higher the growth hormone response to growth hormone releasing hormone the lower the response to bromocriptine and thyrotrophin releasing hormone in acromegaly.
In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.
Acromegaly↗
Escape from dexamethasone-induced ACTH and cortisol suppression by corticotrophin-releasing hormone: modulatory effect of basal dexamethasone levels.
The response of ACTH and cortisol to corticotrophin-releasing hormone (CRH) after pretreatment with various doses of dexamethasone was investigated in five healthy subjects. The five subjects participated in six experiments. In each experiment 200 micrograms ovine CRH was administered as an i.v. bolus injection at 0900 h after pretreatment with respectively: (A) 1 mg dexamethasone orally at 2300 h in the evening before CRH injection, (B) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, (C) 4 mg dexamethasone orally at 2300 h in the evening before CRH injection, (D) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, followed by 2 mg dexamethasone orally 1 h before CRH, (E) no dexamethasone and (F) 1 mg dexamethasone orally 1 h before CRH injection. In spite of overnight suppression with a single dose of dexamethasone CRH elicited cortisol rises in all individuals (experiments A-C). Dexamethasone pretreatment in experiment D abolished the CRH-induced stimulation of the pituitary-adrenal axis. There was a significant and negative correlation between the basal dexamethasone levels (i.e. the dexamethasone levels immediately before CRH administration) in the experiments A-D and the areas under the individual ACTH (R = -0.62; P less than 0.01 by Spearman's rank correlation test) and cortisol (R = -0.81; P less than 0.001 by Spearman's test) curves, i.e. the lower the basal dexamethasone levels, the greater the rise in ACTH and cortisol levels after CRH administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
Early time sequence in pregnenolone metabolism to testosterone in homogenates of human and rat testis.
The time sequence of the metabolism of [4-14C] pregnenolone to testosterone in homogenates of human and rat testis was studied with special emphasis on the chain of events in the early 15 min of incubation. The incubations were performed at 32 C in the presence of NAD and a NADPH-generating system. The various intermediate steroids were separated by means of HPLC using a silica aliphatic diol column. Correction for procedural losses was performed by dual labeling. The present study confirms earlier reported results which showed that in the rat metabolism of pregnenolone to testosterone proceeds via the delta 4 pathway. However, this discloses for the first time that the conversion of pregnenolone proceeds very fast: progesterone, 17 alpha-hydroxyprogesterone, and 17 alpha-hydroxypregnenolone as the only important delta 5 intermediate, peak and decline again to almost undetectable levels within the first 15 min of incubation. Androstenedione and testosterone start to accumulate from 1 min on under the conditions used. In contrast, in the human testis, homogenates metabolism of pregnenolone to testosterone proceeds comparatively slowly and almost exclusively via the delta 5 intermediates dehydroepiandrosterone and androstenediol. Testosterone makes its appearance only after about 8 min of incubation. The data illustrate the importance of short-term incubations in evaluating the metabolism of steroids.
17-alpha-Hydroxypregnenolone↗
The sex pheromone precursor androsta-5,16-dien-3 beta-ol is a major early metabolite in in vitro pregnenolone metabolism in human testicular homogenates.
In an earlier report we described the early time sequence of the in vitro metabolism of [4-14C]pregnenolone ([4-14C]P5) to testosterone in homogenates of human and rat testes and demonstrated the appearance of mainly delta 5 (humans)- and delta 4 (rats)-steroids within minutes after starting the incubation. In this study strong evidence is presented for the substantial synthesis from P5 of the sex pheromone precursor androsta-5,16-dien-3 beta-ol (ADL) in human, but not rat, testicular homogenates. The 16-unsaturated C19 steroid ADL appeared after 1 min of incubation, and within 5 min reached values (17-23% of total radioactivity added as [4-14C]P5) comparable to those of the major delta 5-steroids 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. Thus, in humans, as in boars, the sex attractant precursor ADL is a major early testicular metabolite of P5.
Androstenols↗
The effect of minisomatostatin on anomalous growth hormone responses in acromegaly.
Twelve patients with active acromegaly were treated with the long-acting somatostatin analogue SMS 201-995 at a dose of 50 micrograms sc twice daily in the first 2 weeks of treatment and 100 micrograms twice daily thereafter. Four hours after the first injection of SMS, GH levels became normal in 8 of the 12 patients. The GH response after hpGRF administration was strongly suppressed by SMS. Paradoxical GH responses to TRH disappeared in 6 out of 7 patients during SMS. Paradoxical GH responses to LHR, however, persisted in 4 out of 4 patients. Paradoxical responses of GH after glucose loading disappeared in 2 out of 2 patients. We conclude that SMS normalizes most anomalous growth hormone kinetics in acromegaly. This drug offers a new tool in the treatment of this disease.
Acromegaly↗
Growth hormone responses to the releasing hormones GHRH and GnRH and the inhibitors somatostatin and bromocriptine in TRH-responsive and non-responsive acromegalics.
In acromegalics, the percent peak GH responses to TRH (pTRH) and bromocriptine (pBr) are inversely related with those to GHRH, favouring the hypothesis that in the adenomas of some patients there is a preponderance of GH-producing cells with lactotrope-like characteristics, whereas in others pure somatotropes predominate. The aim of the present study was to investigate whether patients responsive to TRH with allegedly lactotrope-like tumours differ from those patients not responding to TRH with more somatotrope-like adenomas in their answer to the GH inhibitors Br and SRIH and the releasing hormones GHRH and GnRH. The present study demonstrates that the observed reciprocal relations between the GH responses to GHRH, TRH and Br are only present in acromegalics paradoxically responding to TRH (pGHRH vs pTRH -0.73, pGHRH vs pBr -0.60, pTRH vs pBr +0.54, P less than 0.0002-P less than 0.02, N = 20), not in TRH-non-responders (N = 10). In contrast, in these latter patients, not in the former, close relations were found between the percent peak GH responses to GnRH (pGnRH) and pGHRH (r = +0.81, P less than 0.005) and between pGnRH and the percent maximum GH decrements in response to SRIH (pSRIH) (r = +0.64, P less than 0.05). Expectedly, the GH response to Br in the TRH-responders was significantly higher than in the non-responders (75 +/- 4% vs 54 +/- 3%, P less than 0.02), although it was also substantial in the latter. The GH response to SRIH was remarkedly similar in both groups (64 +/- 5 vs 57 +/- 9%, P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Sex difference in growth hormone response to growth hormone-releasing hormone between pubertal tall girls and boys.
In adult rats and also in young adults, a sex difference in GH responsiveness to GHRH has been reported with the higher responses in males. In young rats, however, the reverse has been found, i.e. a higher GH response in females than in males. This discrepancy promoted us to compare GH responsiveness to GHRH in midpubertal tall girls (N = 10) and boys (N = 8). An iv bolus administration of 100 micrograms of GHRH to these adolescents disclosed a sex difference in GH responsiveness. At all time intervals up to 30 min after the bolus, the GH responses to GHRH in the girls were significantly higher than in the boys (P less than 0.025 - P less than 0.05), whereas the peak GH increments (34 +/- 4 vs 19 +/- 3 micrograms/l; P less than 0.02) were about twice as high in the former as in the latter. The data suggest that like in rats, also in humans, sex-related changes in pituitary GH sensitivity to GHRH may be an important factor in the pubertal growth and development at least in tall girls and boys.
Adolescent↗
CRH as a diagnostic and heuristic tool in hypothalamic-pituitary diseases.
The value of CRH as a diagnostic and heuristic tool in hypothalamic-pituitary diseases is discussed. Biochemical and clinical data support the concept that a single bolus injection of CRH can divide patients with secondary adrenal failure into those with hypothalamic and those with pituitary disease. The results of CRH tests in patients with isolated ACTH deficiency suggest a pituitary defect in the majority of patients with this rare disorder. CRH administration in patients with acromegaly and macroprolactinoma demonstrates that the response of the pituitary to CRH is not modulated by high levels of growth hormone or prolactin. CRH can also be used to study the type of the secondary adrenal failure due to exogenous administration of glucocorticoids or endogenous overproduction of cortisol by an adrenal adenoma. The CRH-ACTH axis in man is a highly conserved system with unique characteristics which are a prerequisite to assure vitally important stress reactions.
Acromegaly↗
Long-term treatment of acromegaly with Sandostatin (SMS 201-995). Normalization of most anomalous growth hormone responses.
Twelve patients with active acromegaly were treated with the long-acting somatostatin analogue SMS 201-995 (SMS), at a dose of 50 micrograms sc twice daily in the first 2 weeks of treatment and 100 micrograms sc thereafter. Four h after the first injection of SMS, GH levels became normal in 8 of the 12 patients. Basal glucose levels were significantly lower at the 28th day of treatment. This glucose lowering effect was stronger in the diabetic than in the nondiabetic patients. The postprandial rise of insulin levels was reversed by SMS, leading to a more pronounced postprandial rise of glucose, whereas the postprandial secretion of glucagon was also reversed by SMS. The rise of glucose levels during oral glucose loading was similar before and during SMS, despite a strong inhibitory effect of the drug on the insulin rise after glucose loading. Basal TSH levels were not influenced by SMS, the TRH-induced TSH response, however, was significantly blunted. Although the basal PRL levels were significantly reduced by SMS, the TRH-induced PRL rise was similar before and during administration of the analogue. Paradoxical GH responses to TRH disappeared in 7 out of 8 patients during SMS. Paradoxical GH responses to GnRH, however, persisted in 4 out of 4 patients. Paradoxical responses of GH after glucose loading disappeared in 2 out of 2 patients. The GH response after GHRH administration was strongly suppressed by SMS. During long-term treatment (up to 2 years), the GH level obtained within 5 h after the last injection of SMS remained normal in the patients whose GH levels normalized at the first day of treatment. There was a good response of the disease to this treatment, and no serious adverse reactions were observed. We conclude that SMS normalizes most anomalous growth hormone kinetics in acromegaly. The drug offers a new tool in the treatment of this disease.
Acromegaly↗